Exercise training (EX) induces enhanced endothelium-mediated vasodilation in coronary arterioles in part by increasing endothelial nitric oxide synthase (ecNOS). Endothelium-mediated vasodilation is a complex phenomenon. It appears that increased ecNOS expression is only one mechanism for improved endothelial function. Project 3 will accomplish 4 specific aims and examine endothelium throughout the coronary arterial tree because EX-induced adaptations appear to occur non-uniformly. Aim 1 will test 3 hypothesized mechanisms for improved endothelium-mediated dilation: a) Increased production of PGI/2 via the cyclooxygenase (COX-1); b) Increased expression of cytochrome P450WC11; and c) increased effectiveness of NO due to antioxidant systems. Endothelium function will be measured and pharmacologic, biochemical, and molecular approaches will define expression for enzymes/receptors. Aim 2 will test the hypothesis that shear stress and distention are signals for altered endothelial phenotype in isolated arterioles. Aim 3 is designed to examined endothelial phenotype in arteries of specified size. We propose that endothelial phenotype (and EX-induced changes in endothelial phenotype) in the coronary arterial tree is partially determined by shear stress and wall distention. Aim 4 will test mechanisms hypothesized to be responsible for the ability of EX to restore endothelial function of coronary arteries during hyperlipidemia (HF). Vasomotor responses and biochemical/molecular characterization of endothelial cell phenotype will be used to test the hypothesis that EX reverses HF-induced endothelial dysfunction in coronary arteries through increased expression of ecNOS, COX-1, P450 2C11 isozyme, and/or antioxidant systems. The proposed research will ascertain mechanisms of EX-induced enhancement of endothelial function in coronary arteries and the importance of: 1) arterial diameter, 2) shear stress, and 3) circumferential wall stress (distention). We will also determine mechanisms for effects of EX on endothelial dysfunction during HF. Results will allow integration of these important phenomena in understanding of fundamental processes in vascular adaptation in the coronary circulation. EX-induced improvements in endothelial function may be of central importance to the beneficial effects of exercise training in prevention and treatment of CHD.